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Molecular Characterization of FLT3 Mutations in Acute Leukemia Patients

  • Ishfaq, Mariam (Institute of Molecular Biology and Biotechnology, the University of Lahore) ;
  • Malik, Arif (Institute of Molecular Biology and Biotechnology, the University of Lahore) ;
  • Faiz, Mariam (Molecular Genetics Lab, Department of Pathology, INMOL Hospital) ;
  • Sheikh, Ishfaq Ahmad (King Fahd Medical Research Center) ;
  • Asif, Muhammad (Department of Biotechnology and Informatics, BUITEMS) ;
  • Khan, Muhammad Nasrullah (Allama Iqbal Medical College) ;
  • Qureshi, Muhammad Saeed (Allama Iqbal Medical College) ;
  • Zahid, Sara (Institute of Molecular Biology and Biotechnology, the University of Lahore) ;
  • Manan, Abdul (Institute of Molecular Biology and Biotechnology, the University of Lahore) ;
  • Arooj, Mahwish (Institute of Molecular Biology and Biotechnology, the University of Lahore) ;
  • Qazi, Mahmood Husain (Centre for Research in Molecular Medicine, the University of Lahore) ;
  • Chaudhary, Adeel (Center of Excellence in Genomic Medicine Research (CEGMR), King Abdulaziz University) ;
  • Alqahtani, Mohammed Hussain (Center of Excellence in Genomic Medicine Research (CEGMR), King Abdulaziz University) ;
  • Rasool, Mahmood (Center of Excellence in Genomic Medicine Research (CEGMR), King Abdulaziz University)
  • Published : 2012.09.30

Abstract

Fms-like tyrosine kinase 3 (FLT3) performs a vital role in the pathogenesis of hematopoietic malignancies. Therefore in recent times, the focus of several studies was on use of FLT3 as a prognostic marker. The present study investigated the molecular characterization and incidence of FLT3 mutations in acute leukemia patients in Pakistan. A total of 55 patients were studied, of which 25 were suffering from acute lymphoblastic leukemia (ALL) and 30 were suffering from acute myeloid leukemia (AML). The polymerase chain reaction demonstrated FLT3/ITD mutations in 1 (4%) of 25 ALL patients, a male with the L2 subtype. In AML cases the rate was 4 (13.3%) of 30, three males and one female. The AML-M4 subtype was found in three and the AML M2 subtype in the other. In the AML cases, a statistically significant (p=0.009) relationship was found between WBC (109/L) and FLT3/ITD positivity. However, no significant relationship was found with other clinical parameters (p>0.05). In acute myeloid leukemia (AML) $FLT3/ITD^+$ mutation was more prevalent in elderly patients 31-40 age groups, 21-30 and 51-60 age groups respectively. In acute lymphoblastic leukemia (ALL) statistically no significant relationship was found between clinical features and FLT3/ITD positivity (p>0.05). However, in acute lymphoblastic leukemia (ALL) $FLT3/ITD^+$ mutation was more commonly found in age groups of 21-30.

References

  1. Abu-Duhier FM, Goodeve AC, Wilson, GA (2000). FLT3 internal tandem duplication mutations in adult acute myeloid leukaemia define a high-risk group. Br J Haematol, 111, 190-5. https://doi.org/10.1046/j.1365-2141.2000.02317.x
  2. Brunet S, Labopin M, Esteve J, et al (2012). Impact of FLT3 internal tandem duplication on the outcome of related and unrelated hematopoietic transplantation for adult acute myeloid leukemia in first remission: a retrospective analysis. J Clin Oncol, 30, 735-41. https://doi.org/10.1200/JCO.2011.36.9868
  3. Govedarovic N, Marjanovic G (2011). Frequency and prognostic impact of FLT3/ITD mutation in patients with acute myeloid leukaemia. J BUON. 16, 108-11.
  4. Grimberg J, Nawoschik S, Belluscio L, et al (1989). A simple and efficient non-organic procedure for the isolation of genomic DNA from blood. Nucleic Acid Res, 17, 8390.
  5. Karabacak, BH, Erbey F, Bayram I, et al (2010). Fms-like tyrosine kinase 3 mutations in childhood acute leukemias and their association with prognosis. Asian Pac J Cancer Prev, 11, 923-7.
  6. Kiyoi H, Naoe T, Nakano Y (1999). Prognostic implication of FLT3 and N-RAS gene mutations in acute myeloid leukemia. Blood, 93, 3074-80.
  7. Kiyoi H, Towatari M, Yokota S (1998). Internal tandem duplication of the FLT3 gene is a novel modality of elongation mutation which causes constitutive activation of the product. Leukemia, 12, 1333-7. https://doi.org/10.1038/sj.leu.2401130
  8. Kottaridis PD, Gale RE, Frew ME, et al (2001). The presence of a FLT3 internal tandem duplication in patients with acute myeloid leukemia (AML) adds important prognostic information to cytogenetic risk group and response to the first cycle of chemotherapy: analysis of 854 patients from the United Kingdom medical research council AML 10 and 12 trials. Blood, 98, 1752-9. https://doi.org/10.1182/blood.V98.6.1752
  9. Kutny MA, Moser BK, Laumann K, et al (2012). FLT3 mutation status is a predictor of early death in pediatric acute promyelocytic leukemia: Pediatr. Blood Cancer, 59, 662-7. https://doi.org/10.1002/pbc.24122
  10. Meshinchi S, Woods WG, Stirewalt DL (2001). Prevalence and prognostic significance of flt3 internal tandem duplication in pediatric acute myeloid leukemia. Blood, 97, 89-94. https://doi.org/10.1182/blood.V97.1.89
  11. Peng HL, Zhan GS, Gong FJ (2008). Fms-like tyrosine kinase (FLT)3 and FLT3 internal tandem duplication in different types of adult leukemia: Analysis of 147 patients. Croat Med, 49, 650-9. https://doi.org/10.3325/cmj.2008.5.650
  12. Rollins-Raval M, Pillai R, Warita K, et al (2012). CD123 Immunohistochemical expression in acute myeloid leukemia is associated with underlying FLT3-ITD and NPM1 mutations. Appl Immunohistochem Mol Morphol. 2012 Aug 20 (Epub ahead of print).
  13. Ruan M, Wang YQ, Zhang L, et al (2011). FLT3 mutations in children with acute myeloid leukemia: a single center study. Zhongguo Dang Dai Er Ke Za Zhi, 13, 863-6.
  14. Sambrook J, Russel DW (2001). Gel electrophoresis of DNA and pulsed-field agarose. A laboratory manual. Molecular Cloning, 1, 133.
  15. Stirewalt DL, Radich JP (2003). The role of FLT3 in hematopoietic malignancies. Nat Rev Cancer, 3, 650-65. https://doi.org/10.1038/nrc1169
  16. Taketani T, Taki T, Sugita K, et al (2004). FLT3 mutations in the activation loop of tyrosine kinase domain are frequently found in infant ALL with MLL rearrangements and pediatric ALL with hyperdiploidy. Blood, 103, 1085-8.
  17. Thied C, Steudel C, Mohr B, et al (2002). Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia association with FAB subtypes and identification of subgroups with poor prognosis. Blood, 99, 4326-35. https://doi.org/10.1182/blood.V99.12.4326
  18. Turner AM, Lin NL, Issarachai S, Lyman SD, Broudy VC (1996). FLT3 receptor expression on the surface of normal and malignant human hematopoietic cells. Blood, 88, 3383-90.
  19. Wang L, Zhou C, Zhang X, Wang M (2004). Prevalence and clinical significance of FLT3 internal tandem duplication mutation in acute leukemia. Zhonghua Xue Ye Xue Za Zhi, 25, 393-6.
  20. Williams AB, Li L, Nguyen B, et al (2012). Fluvastatin inhibits FLT3 glycosylation in human and murine cells and prolongs survival of mice with FLT3/ITD leukemia. Blood, ?, ?-?.
  21. Williams AB, Nguyen B, Li L, et al (2012). Mutations of FLT3/ ITD confer resistance to multiple tyrosine kinase inhibitors. Leukemia, 10, 191.
  22. Xu F, Taki T, Yang HW, et al (1999). Tandem duplication of the FLT-3 gene is found in acute lymphoblastic leukemia as well as acute acute myeloid leukemia but not in myelodysplastic syndrome or juvenile chronic myelogenous leukemia in children. Br J Haematol, 105, 155-62. https://doi.org/10.1111/j.1365-2141.1999.01284.x
  23. Zakar F, Mohammadzadeh M, Mohammadi M (2010). Detection of KIT and FLT3 mutation in acute myeloid leukemia with different subtypes. Arch Iran Med, 13, 21-5.

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